The risks and benefits of patients temporarily discontinuing medications in the event of an intercurrent illness: a systematic review protocol

Andrew Morden1 2*, Jeremy Horwood1 2, Penny Whiting 1 2, Jelena Savovic1 2, Laurie Tomlinson3,

Thomas Blakeman4 5, Charles Tomson6, Alison Richards1 2, Tracey Stone1 2, Fergus Caskey2 7

1NIHR CLAHRC West.

2School of Social and Community Medicine, University of Bristol

3Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine

4Centre for Primary Care, Institute of Population Health, The University of Manchester

5NIHR CLAHRC Greater Manchester

6Department of Renal Medicine, Freeman Hospital, Newcastle Upon Tyne Hospitals Foundation Trust

7UK Renal Registry

*Corresponding author: NIHR CLAHRC West, 9th Floor Whitefriars, Lewins Mead, Bristol, BS1 9NT, UK. Email: andrew.morden@bristol.ac.uk. Telephone: 44 117 3421244

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ABSTRACT

Background

Acute kidney Injury (AKI) is common and often leads to significant morbidity and / or death. The development of AKI, or complications associated with it, may be due to use of certain medications in at risk patients experiencing an intercurrent illness. Implicated drugs include diuretics, angiotensin-converting-enzyme inhibitors/ angiotensin receptor blockers / direct renin inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), metformin and sulfonylureas. Expert consensus opinion (and clinical guidelines) recommend considering discontinuation of diuretics, angiotensin-converting-enzyme inhibitors/ angiotensin receptor blockers / direct renin inhibitors, NSAIDs, metformin and sulfonylureas in the event of an intercurrent illness to prevent AKI onset or reduce severity or complications. However, the evidence base for these recommendations is very limited. This systematic review aims to address the available evidence for the temporary discontinuation of diuretics, ACE inhibitors, angiotensin receptor blockers, direct renin inhibitors, non-steroidal anti-inflammatories and metformin and sulfonylureas for those at risk of AKI or with newly diagnosed AKI.

Methods/design

Randomized controlled trials, non-randomized trials, cohort studies, case-control studies, interrupted time-series studies, before-and-after studies featuring adults aged 18 and over in any setting currently taking diuretics, angiotensin-converting-enzyme inhibitors/ angiotensin receptor blockers / direct renin inhibitors, NSAIDs, metformin, and experiencing an intercurrent illness or undergoing a radiological/surgical procedure (planned or unplanned) will be searched for. Relevant trial registers and systematic review databases will be searched. Systematic reviews will be assessed for methodological quality using the ROBIS tool, trials will be assessed using the Cochrane Risk of Bias tool, and observational studies will be assessed using the ACROBAT-NRS tool. If sufficient studies assessing similar populations, study type, settings and outcomes are found then a formal meta-analysis will be performed to estimate summary measures of effect. If not a narrative synthesis will be adopted.

Discussion

This review will synthesize evidence for the efficacy of discontinuing diuretics, angiotensin-converting-enzyme inhibitors/ angiotensin receptor blockers / direct renin inhibitors, NSAIDs, metformin or sulfonylureas to prevent or delay onset of AKI or associated complications. Results will provide guidance on efficacy and safety of this strategy and potentially help to develop an intervention to test the best mechanism of guiding medication discontinuation in at risk populations.

Systematic review registration

PROSPERO CRD42015023210

Keywords:

Acute Kidney injury, medication discontinuation, sick day rules, diuretics, angiotensin-converting-enzyme inhibitors, angiotensin receptor blockers, direct renin inhibitors, NSAID, metformin and sulfonylureas.

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Background

Acute kidney injury (AKI) is a comparatively recent term describing a sudden reduction in renal

excretory function. The term was introduced because of a lack of agreement about what

compromised ‘acute renal failure’, with some definitions only including the requirement for renal

replacement therapy. The causes of AKI can be divided into three groups: pre-renal, such as low

blood pressure; intrinsic renal, commonly the result of prolonged sepsis or hypotension but also

resulting from immune conditions affecting the kidney; and post-renal, caused by partial or complete

obstruction to the flow of urine from the kidneys [1]. There are a number of key risk factors for AKI,

including: existing chronic kidney disease (CKD), age >65years, , cardiac failure, liver disease,

diabetes mellitus, use of nephrotoxic drugs such as non-steroidal anti inflammatories (NSAIDs) and

aminoglycosides, hypotension (compared to baseline blood pressure) and sepsis, neurological or

cognitive impairment or disability or prior urological obstruction [1, 2]. An episode of AKI may be

triggered by an intercurrent illness, such as diarrhoea and vomiting, influenza, other viruses, urinary

tract infections, respiratory tract infections, skin infections and hypovolaemia from any cause in

those most at risk [1, 3].

The pooled incidence rate of AKI globally is 21.6% in adults [4] and AKI is predicted to feature in 1-7%

of hospital admissions [1, 3, 5-7]. The morbidity and mortality rates associated with an episode of

AKI (in hospital and after discharge) are high [6, 8-10]. Coca et al’s systematic review reports that the

incidence of CKD and end-stage kidney disease (ESKD) after an AKI episode is 7.8 and 4.9/100

patient-years, respectively, and that AKI is associated with long term mortality [10].

Pannu and colleagues review the potentially harmful biochemical effects of medications that are

administered as part of the routine care of critical illnesses in hospital settings and conclude that

many, such as such as ACE inhibitors and NSAIDS, could be detrimental to kidney function [9].

Medication induced episodes of kidney problems are increasingly prevalent and indeed doubled

between 1999-2009 in the UK [11]. Commonly prescribed medications including diuretics,

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angiotensin-converting-enzyme (ACE) inhibitors / angiotensin receptor blockers / direct renin

inhibitors, NSAIDs , metformin, and sulfonylureas have been associated with AKI (and related

complications) in a variety of settings [12-30]. The incidence of AKI is higher amongst patients who

have multiple comorbidities and are taking combinations of drugs which may interact to enhance the

physiological insult underlying AKI [31].

Expert consensus statements and clinical guidelines have recommended that clinicians temporarily

withhold potentially harmful medications for high risk patients when they develop an intercurrent

illness to reduce risk of AKI [1-3]. Other interventions have gone further by suggesting that patients

stop the medications when they become unwell [32]. However, there is surprisingly little evidence to

support these recommendations. The NICE guidelines issued in 2013 found no studies which

evaluate the efficacy of medication discontinuation during an intercurrent illness in terms of

preventing onset or harm from AKI [2]. There is growing concern regarding the overall risks and

benefits of the sick-day rules approach [33]. Such advice could lead to an increase in complications

from the conditions which the drugs are prescribed such as heart failure and hypertension. NSAIDs

are recommended for pain control, especially for osteoarthritis pain in older adults [34]; cessation

of NSAIDs may result in a marked reduction in mobility and make the difference between a person

coping at home or not. In addition, it is suggested that continuing some of these drugs will have

renal and cardiac benefits, even in the presence of AKI, at least in some patients. ACE Inhibitors and,

angiotensin receptor blockers / direct renin inhibitors, for instance, preserve tubular blood flow and

may prevent the tubular injury that characterises the transition from reversible pre-renal AKI to

established, intrinsic renal AKI, which has a poorer prognosis [35].

Therefore, the overall objective of this review is to assess the available evidence for the temporary

discontinuation of diuretics, ACE inhibitors, angiotensin receptor blockers, direct renin inhibitors,

non-steroidal anti-inflammatories, metformin and sulfonylureas in adults in primary and secondary

care at risk of AKI or with newly diagnosed AKI as a result of an intercurrent illness or a radiological /

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surgical procedure (planned or unplanned). To address this objective we will answer the following

review questions:

1.) What are the effects of temporary discontinuation of diuretics, angiotensin-converting-

enzyme inhibitors/ angiotensin receptor blockers / direct renin inhibitors, NSAIDs,

metformin, and sulfonylureas in those at risk of AKI?

2.) What are the effects of the temporary discontinuation of diuretics, angiotensin-converting-

enzyme inhibitors/ angiotensin receptor blockers / direct renin inhibitors, NSAIDs,

metformin, sulfonylureas for the progression of AKI across AKI severity categories?

3.) What are the adverse effects associated with stopping diuretics, angiotensin-converting-

enzyme inhibitors/ angiotensin receptor blockers / direct renin inhibitors, NSAIDs,

sulfonylureas, and metformin?

4.) What is the effectiveness of interventions to encourage stopping of diuretics, angiotensin-

converting-enzyme inhibitors/ angiotensin receptor blockers / direct renin inhibitors,

NSAIDs, metformin, and sulfonylureas?

Methods

Systematic review methods will follow the principles outlined in the Centre for Reviews and

Dissemination (CRD) guidance for undertaking reviews in health care [36] and the Cochrane

Handbook [37]. The protocol is registered on the PROSPERO database (CRD42015023210). The

review will be reported according to the PRISMA guidelines [38, 39]. This protocol follows the

PRISMA-P reporting guidelines [40].

Eligibility criteria

Studies that fulfil the following criteria will be eligible for inclusion:

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Types of studies

Randomized controlled trials, non-randomized trials, cohort studies, case-control studies,

interrupted time-series studies, before-and-after studies. If high quality systematic reviews are

identified that fulfil all inclusion criteria for the review then these will be eligible for inclusion. We

will include the systematic review if it includes all relevant studies for a single research question; if

additional studies fulfil our inclusion criteria then the original review will be used only as a source of

relevant studies.

Participants

Only studies conducted in humans will be sought. Adults aged 18 and over in any setting (e.g.

community, GP surgery, hospital) currently taking diuretics, ACE inhibitors, angiotensin receptor

blockers, direct renin inhibitors, non-steroidal anti-inflammatories, metformin or sulfonylureas

experiencing an intercurrent illness or undergoing a radiological/surgical procedure (planned or

unplanned).

Interventions

Temporary discontinuation of diuretics, angiotensin-converting-enzyme inhibitors/ angiotensin

receptor blockers / direct renin inhibitors, NSAIDs, metformin and sulfonylureas as a result of a

specific intervention or for any other reason. Eligible comparator interventions (if present) will be

placebo, no treatment or usual care.

Outcomes and comparators

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The review will be restricted to studies that report some measure of kidney function. We anticipate

that other relevant outcomes will include all-cause mortality, cardiac events, diabetic events, and

pain related outcomes (pain severity, use of GP services or admission to hospital relating to NSAID

withdrawal).

Search Strategy

Attempts will be made to identify relevant studies on temporarily discontinuing diuretics,

angiotensin-converting-enzyme inhibitors/ angiotensin receptor blockers / direct renin inhibitors,

NSAIDs, metformin, and sulfonylureas. Search methods will meet best practice standards in

systematic reviews [36, 37]. The search strategies will be developed specifically for each database

and the keywords adapted according to the configuration of each database. Searches will not be

limited by language, date or publication status (unpublished or published). Searches will be

performed in multiple databases from inception to present, including: Embase (OvidSP), Medline

(OvidSP), Medline In-Process Citations & Daily Update (OvidSP), PsycINFO (OvidSP), BIOSIS Citation

Index (Web of Science), CINAHL (Cumulative Index to Nursing and Allied Health Literature) (EBSCO),

Science Citation Index (SCI) (Web of Science), and Cochrane Central Register of Controlled Trials

(CENTRAL) (Wiley).

Supplementary searches will be undertaken to identify grey literature, completed and ongoing trials,

in resources such as: NIH ClinicalTrials.gov (http://www.clinicaltrials.gov), metaRegister of

Controlled Trials (http://www.controlled-trials.com), WHO International Clinical Trials Registry

Platform (ICTRP) (http://www.who.int/ictrp/en), relevant guidelines (i.e. NICE in the UK) regarding

management of AKI, and references of published articles found in the search. An example of the

search strategy is presented in appendix 1.

Identified references will be downloaded into Endnote X7 software for further assessment and

handling. Rigorous records are maintained as part of the searching process. Individual records within

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the Endnote reference libraries will be tagged with search information, such as searcher, date

searched, database host, database searched, strategy name and iteration, theme or search question.

This will enable the information specialist to track the origin of each individual database record, and

its progress through the screening and review process. A review specific access database will be used

to manage screening and data extraction.

Selection of studies

Two reviewers will independently screen the titles and abstracts of all reports identified by searches

and any discrepancies will be discussed and resolved by consensus. Full copies of all studies deemed

potentially relevant will be obtained and the same two reviewers will independently assess these for

inclusion; any disagreements will be resolved by consensus.

Data extraction

Data extraction will be carried out using standard data extraction forms designed specifically for this

review. Data will be extracted by one reviewer, using a piloted, standard data extraction form and

checked by a second; any disagreements will be resolved by consensus. Data will be extracted on the

following: participant characteristics; study design; inclusion and exclusion criteria; details of

intervention (if applicable - potentially including an outline of the characteristics of the interventions

in terms of the 1) format and content of any 'sick day rules' advice as well as 2) whether part of a

wider package of care. i.e. in the context of other AKI/kidney health initiatives), details of outcomes

assessed (primary and other outcomes measures), results. If, during the course of the review,

outcome measures commonly reported in studies are found these will be included and documented

[40].

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Quality assessment

Systematic reviews will be assessed for risk of bias using the ROBIS tool [41]: this tool aims includes

domains covering study eligibility criteria, identification and selection of studies, data collection and

study appraisal, synthesis and findings, and interpretation. Trials will be assessed for methodological

quality using the Cochrane Risk of Bias tool [37]. This includes items covering selection bias (random

sequence generation and allocation concealment), performance bias (participant blinding), detection

bias (blinding of outcome assessors) attrition bias (incomplete outcome data), and reporting bias

(selective reporting). There is also an additional field for other sources of bias. We believe that all

important concerns about bias are included in the other domains in the tool and so no further

domains will be added. We will use the new ACROBAT-NRS tool to assess the risk of bias in

observational studies [42]. It includes domains covering bias due to confounding, bias in the

selection of participants into the study, bias due to departures from intended interventions, bias due

to missing data, bias in taking measurements, and bias in selection of the reported result. For all

tools, if at least one of the domains is rated as “high” the study will be considered at high risk of bias,

if all domains are judged as “low” the trial will be considered at low risk of bias, otherwise the trial

will be considered at “unclear” risk of bias. The risk of bias assessment will be conducted as part of

the data extraction process.

Data synthesis

A narrative summary of the included studies will be presented. This will include a summary of the

characteristics (e.g. study design, intervention (if applicable), population size, geographical location,

settings (community, hospital, or other healthcare setting), year, baseline population characteristics,

and outcome definition. If data are considered too heterogeneous to pool, or not reported in a

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format suitable for pooling (e.g. data reported as medians) then we will employ a narrative

synthesis. This will involve the use of descriptive text and tables to summarise data in order to allow

the reader to consider outcomes in the light of differences in study designs and potential sources of

bias for each of the studies being reviewed. This involves organising the studies by (as appropriate)

population, outcomes assessed, type of study, and study settings, summarising the results of the

studies, summarising the range and size of the associations these studies report, and describing the

most important characteristics of the included studies. A detailed commentary on the major

methodological problems or biases that affected the studies will also be included, together with a

description of how this has affected the individual study results.

If sufficient studies assessing similar populations, study type, settings and outcomes are found then a

formal meta-analysis will be used to estimate summary measures of effect. For dichotomous data

we will calculate the relative risk (RR) for each study with the associated 95% confidence intervals.

Continuous data will be analysed as the mean difference between groups and associated 95%

confidence intervals. For multi-arm studies, we will analyse each intervention arm compared to the

control group separately.

We anticipate that systematic differences between studies (heterogeneity) will be likely. Therefore,

the random-effects model will be used to calculate summary estimates. Heterogeneity will be

investigated visually using forest plots and statistically using the I2 and Q statistics [43].

Heterogeneity will be formally investigated using meta-regression analyses, where sufficient data are

available. We anticipate that the effects of the following variables will be investigated:

methodological quality of the primary studies, how the advice or decision to discontinue

medications was administered and length of medication discontinuation, age, sex, and

comorbidities. Other variables considered relevant on further examination of the literature or input

from clinical experts may also be considered. The coefficient describing the effect of each variable on

the outcome will be modelled, using a random effects model.

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If appropriate, small study effects (publication bias) will be assessed using a modified linear

regression test for funnel plot asymmetry as recommended where there are sufficient numbers of

trials (i.e. six trials) [44].

Confidence in cumulative evidence

We will consider using the GRADE guidelines [45] to help us evaluate the cumulative quality of the

evidence reported in this review for risk of bias, publication bias, imprecision, inconsistency,

indirectness, and magnitude of effect.

Discussion

Diuretics, angiotensin-converting-enzyme inhibitors, angiotensin receptor blockers, direct renin

inhibitors, NSAIDs, metformin and sulfonylureas) in at risk patients experiencing an intercurrent

illness are extremely commonly prescribed and expert consensus (subsequently incorporated into

clinical guidelines) recommends the discontinuation of these medications for individuals at risk of

AKI during an intercurrent illness. The benefit from such advice is however unproven with scant

evidence regarding the benefits and potential harms that discontinuation may confer. An up-to-date

systematic review of the evidence on discontinuing medications is warranted. This review will

provide evidence on the effectiveness and safety of discontinuing diuretics, angiotensin-converting-

enzyme inhibitors/ angiotensin receptor blockers / direct renin inhibitors, NSAIDs, metformin and

sulfonylureas in relation to AKI. We anticipate that the findings will aid health care practitioners and

policymakers in developing recommendations regarding advice on temporary drug cessation in

patients at risk of AKI. Furthermore, the findings will benefit researchers by highlighting future

research directions through the identification of gaps in knowledge and shortcomings of the existing

evidence base.

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Abbreviations

ACE - angiotensin-converting-enzyme

AKI – Acute Kidney Injury

CKD – Chronic Kidney Disease

CRD – Centre for Reviews and Dissemination

NSAIDS – Non-steroidal anti-inflammatory drugs

ESKD – End Stage Kidney Disease

NICE – National Institute for Health and Clinical Excellence

Competing interests

The authors declare that they have no competing interests.

Author contributions

CT, TB and FC conceived the idea for the review. AM drafted the written protocol with the support of

FC, JS, PW and JH. All authors contributed to the development of the protocol. PW, JS, and AR

provided input on study methodology. FC served as a content expert in the field of AKI. JH served as

the overall supervisor and provided input on study methodology. AM, TS and AR will be involved in

data acquisition. AM and TS will be undertaking screening and data extraction. All authors will

contribute to data analysis and the interpretation of results. AM will draft the final manuscript

intended for publication. All authors have given their approval for publication.

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Acknowledgements

This research is supported by the National Institute for Health Research (NIHR) Collaboration for

Leadership in Applied Health Research and Care West at University Hospitals Bristol NHS Foundation

Trust. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR

or the Department of Health.

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